Structure-based design, synthesis and bioactivity evaluation of macrocyclic inhibitors of mutant isocitrate dehydrogenase 2 (IDH2) displaying activity in acute myeloid leukemia cells

  • Eur J Med Chem. 2020 Oct 1;203:112491. doi: 10.1016/j.ejmech.2020.112491.
Jinxin Che  1 ,  Feng Huang  1 ,  Mengmeng Zhang  2 ,  Gaoya Xu  2 ,  Bingxue Qu  1 ,  Jian Gao  1 ,  Binhui Chen  1 ,  Jianjun Zhang  3 ,  Huazhou Ying  1 ,  Yongzhou Hu  1 ,  Xiaobei Hu  2 ,  Yubo Zhou  2 ,  Anhui Gao  4 ,  Jia Li  5 ,  Xiaowu Dong  6
Affiliations
  • 1. ZJU-ENS Joint Laboratory of Medicinal Chemistry, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Hangzhou Institute of Innovative Medicine, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, PR China.
  • 2. National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, PR China.
  • 3. Department of Pharmacy, The First Affiliated Hospital of Zhejiang Chinese Medical University, Zhejiang Provincial Hospital of Traditional Chinese Medicine, Hangzhou, 310058, PR China.
  • 4. National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, PR China. Electronic address: [email protected].
  • 5. National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, PR China; Open Studio for Druggability Research of Marine Natural Products, Pilot National Laboratory for Marine Science and Technology (Qingdao), 1 Wenhai Road, Aoshanwei, Jimo, Qingdao, 266237, PR China. Electronic address: [email protected].
  • 6. ZJU-ENS Joint Laboratory of Medicinal Chemistry, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Hangzhou Institute of Innovative Medicine, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, PR China. Electronic address: [email protected].
PMID: 32679449 DOI: 10.1016/j.ejmech.2020.112491
Abstract

The Enzymes involved in the metabolic pathways in Cancer cells have been demonstrated as important therapeutic targets such as the isocitrate dehydrogenase 2 (IDH2). A series of macrocyclic derivatives was designed based on the marketed IDH2 Inhibitor AG-221 by using the conformational restriction strategy. The resulted compounds showed moderate to good inhibitory potential against different IDH2-mutant Enzymes. Amongst, compound C6 exhibited better IDH2R140Q inhibitory potency than AG-221, and showed excellent activity of 2-hydroxyglutarate (2-HG) suppression in vitro and its mesylate displayed good pharmacokinetic profiles. Moreover, C6 performed strong binding mode to IDH2R140Q after computational docking and dynamic simulation, which may serve as a good starting point for further development.

Keywords
Conformational restriction; Inhibitors; Isocitrate dehydrogenase 2; Macrocyclic derivatives; Metabolic pathways.
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